Precapillary Sphincters Research Articles

Intestinal O2 uptake during sympathetic stimulation and partial arterial occlusion

In isolated loops of canine small bowel perfused at constant blood flow, stimulating perivascular sympathetic nerves (8--10 Hz) depressed O2 extraction and O2 uptake. Because sympathetic stimulation also decreased 86Rb extraction, the results confirmed earlier studies indicating that sympathetic stimulation closes "precapillary sphincters" and through diffusion limitations reduces the capillary-to-cell flux of oxygen. To determine if sympathetic stimulation could lower O2 uptake under more physiologic circumstances, a second series of experiments was performed during constant arterial pressure perfusion. Sympathetic stimulation reduced blood flow by about 30% in the steady phase. Oxygen extraction did not increase appreciably, so O2 uptake was also reduced. When partial arterial occlusion was used to lower the blood flow to the level that it reached during sympathetic stimulation, large increases (37%) in O2 extraction occurred so that O2 uptake remained near control levels. The results indicate that after arterial occlusion local mechanisms maintain O2 uptake by increasing O2 extraction through capillary density increases, but that this mechanism is impaired by sympathetic stimulation.

Scanning electron microscopy of microcorrosion casts; intracranial and abdominal microvasculature in domestic animals.

The use of methyl methacrylate corrosion casts prepared for portions of the vascular system has made it possible to examine numerous and extensive areas of microscopic structures on a 3-dimensional scale with the scanning electron microscope. By this means we have examined the arterial microvasculature of intracranial vessels among three domestic animal species. In addition, these vessels have been compared with the terminal branches of abdominal arteries in the dog. The results of this study suggest that the sphincteric control mechanisms of the vessels in the two regions may be structurally different from one another. In the case of the intracranial vessels, the terminal portion of the arteriole is continued by a precapillary arteriole composed of a chain-like series of muscular constrictions. This is most suitably described as a precapillary sphincter area, which terminates at the capillary. In the abdominal vessels, the precapillary arteriole is generally followed by a single precapillary sphincter at the origin of the capillary. These morphological characteristics may account, in part, for the difference in response of vessels in these two regions in hypovolemic shock.

Frequency analysis of coronary intercapillary distances: site of capillary control.

Frequency distributions for minimum intercapillary distance (ICD) and functional ICD were characterized for rat heart in situ. Minimum ICD denotes spacings between adjacent capillaries whether they contain erythrocytes or not. Functional ICD is defined as spacings between contiguous capillaries perfused with erythrocytes. Minimum ICD was well fitted by both the gamma and the lognormal distributions. Functional ICD was well fitted by the lognormal, but not by the gamma, or by any mixture of the gamma with another discrete distribution. The frequency analysis is interpreted to mean that: 1) A control site distal to the true arteriole exists. This is presumably the precapillary sphincter. 21 Intercapillary anastomoses help keep the diffusion path in myocardium short and comparatively uniform. 3) Complete closure of arterioles does not occur in the unstressed heart. 4) Blood flow and conditions for diffusion can be controlled independently.

Capillary spacing around coronary venules suggests that diffusion distance is controlled by local tissue pO 2

O 2 diffuses from venules (Davies and Bronk, Fed. Proc. 16, 689–692). To learn whether the O 2 diffusion field around venules influences adjacent precapillary sphincters we measured the mean distance from a venule to the first adjacent capillary in rat hearts beating in situ. This distance was 1.97 μm less than the distance from that capillary to the next capillary in the array ( P < 0.05). This and supporting evidence is interpreted to mean that: (a) Coronary precapillary sphincters can be influenced by local tissue pO 2. (b) The system which sets intercapillary distance is capable of very local short-range control.

Hepatic presinusoidal sphincters affected by altered arterial pressure and flow, venous pressure, and nerve stimulation

Alterations in hepatic circulation and oxygen uptake were monitored using an intact feline liver preparation with arterial and portal blood flows measured separately and hepatic venous pressure under experimental control. Oxygen extraction ratios, if interpreted cautiously, can be used to indicate sphincter-like control of diffusion parameters in the tissues. Presinusoidal (precapillary) sphincters do not alter fluid exchange parameters in the liver. The results shown here are interpreted as providing evidence that sphincters or sphincter-like segments of the hepatic vasculature do, however, affect diffusion parameters. Constriction of sphincters is associated with a reduced oxygen extraction ratio, dilation with increased extraction. The sphincters are initially constricted by hepatic nerve stimulation but show a secondary dilation due to maintained reduction in conductance of the hepatic artery (upstream). Sphincter dilation, indicated by increased oxygen extraction under selective experimental conditions, was suggested. Elevations in arterial blood pressure produced myogenic arterial constriction which resulted in secondary sphincter dilation. Similarly, graded occlusion of the hepatic artery resulted in sphincter dilation. Sphincters appear to be controlled by blood flow changes since oxygen extraction changes were correlated with changes in blood flow but not with changes in hepatic oxygen delivery. Myogenic stimuli do not appear to affect sphincters since elevated hepatic venous pressure did not cause sphincter constriction, nor did in impair oxygen uptake.

Fluid transfer from skeletal muscle to blood during hemorrhage Importance of beta adrenergic vascular mechanisms

Vascular reactions in the cat lower leg in response to short-term (10 min) hemorrhagic hypotension (approximately 80 mmHg) were studied before and after regional blockade of the beta-adrenoceptors. In the muscle region with intact beta-adrenoceptors, hemorrhage raised vascular resistance by about 80% and caused a dilatation of the precapillary sphincters, the latter effect evidenced in terms of a 35% increase of the capillary filtration coefficient. Concomitantly, an absorption of extravascular fluid to the blood stream occurred, a process tending to compensate for the reduction of intravascular fluid volume. After regional beta-blockade there was quite a marked augmentation of the hemorrhage induced increase of vascular resistance whereas the inhibition of precapillary sphincter tone and the transcapillary fluid absorption were almost abolished. These observations indicate that bleeding is associated with a significant beta-adrenergic dilator influence in both the resistance vessels and precapillary sphincters of skeletal muscle and that the beta-dilator mechanism may be essential for the important, compensatory fluid gain from the extravascular to the intravascular space during hemorrhage. The observed beta-adrenergic mediation of the net transcapillary fluid absorption could be ascribed to resetting of the pre-/postcapillary resistance ratio, leading to decreased capillary hydrostatic pressure, and to the dilator influence in the precapillary sphincters, leading to an increased number of the patent capillaries available for the transcapillary fluid exchange.

Microscopic anatomy of the pulmonary vascular bed in the cat lung

The pulmonary microcirculation of the cat was analyzed by light and electron microscopy. In order to establish the precise structure and ultrastructure of the components of the vascular wall of each segment, special efforts were made to identify positively the pulmonary arterioles and venules by tracing their connection to small pulmonary arteries and veins, respectively. Also, the pulmonary arterioles and venules were studied with respect to their relationship to the alveolar capillary network via the precapillary sphincter areas and the postcapillary venules. It was confirmed that the small pulmonary arteries, arterioles, and precapillary sphincter areas are provided with smooth muscle cells which are present up to the point where the pulmonary capillaries branch out, although the number of smooth muscle cells decreases gradually toward the capillary bed. Cholinergic and noradrenergic nerves accompany all arterial segments. The capillary network described by many investigators in several mammalian species was studied only to the extent that a three-dimensional conceptualization could be obtained. With respect to the postcapillary venules and pulmonary venules, it was discovered that, in the cat lung, true smooth muscle cells, albeit widely scattered, are present in these segments of the pulmonary microcirculation. These smooth muscle cells display extensive areas of myoendothelial junctions. That is, the cell membranes of the endothelial cells and the smooth muscle cells make contact without an intervening basal lamina. Some myoendothelial junctions were identified also in the arterioles and precapillary sphincter areas. However, they were few in number and had points of only limited membrane contact. The functional implications of these findings are discussed in terms of possible regulatory influence on the pulmonary microcirculation and hypothetical role in the development of pulmonary hypertension.

Central neural influence on precapillary microvessels and sphincter.

The responses to central nervous system (CNS) stimulation of consecutive segments of arterioles down to the precapillary sphincter were measured in the mesoappendix and/or cremaster of nine male rats with indwelling electrodes. Under pentobarbital sodium anesthesia, vasoactive sites were stimulated at threshold for maximal constriction or lumen closure of the precapillary sphincter and/or immediately preceding precapillary arteriole (metarteriole). In all experiments, CNS stimulation induced blood pressure elevation and constriction of three consecutive segments of precapillary vessels and of the sphincter. A threefold increase in rate of vasomotion of precapillary sphincter and metarteriole was the rule, but this was noted infrequently in larger arterioles. In addition to an overall influence of the CNS on microcirculation, the data show a gradient of responses to stimulation, the slope of which is negatively related to the size of the vessels and sphincter, in both tissues studied. A complete lumen closure of the metarteriole and precapillary sphincter (when present) in response to CNS stimulation implies active participation in the regulation of local blood flow. No evidence was foun for central neural regulation of the precapillary sphincter independent of arteriolar control.

Responses of the leptomeningeal microcirculation to hypothalmic stimulation

Studies were made on the effects of hypothalamic stimulation on the cerebral blood supply system at the parietal and parieto-occipital regions. Magnification angiography with and without fluorescein, radioactive krypton, and heat clearance techniques were used. Stimuli were delivered through bipolar stainless-steel needle electrodes using 15-sec train stimuli of 0.5-msec-wide square waves at a 100/sec pulse repetition rate and close to threshold intensities. It was found that stimulation of specific hypothalamic sites causes an immediate transient opening or somesimes closing of microvessel beds. This effect appears to be mediated by a vasoactive neurogenic mechanism presumably exerted on precapillary arterioles or possibly precapillary sphincters. This assumption was made on the grounds that in many cases the microvessel volume changes took place even without significant alterations in systemic blood pressure. Adaptation phenomena were observed in each case: Just as the effect on the microvessel beds reached its maximum and even while the stimulation continued, there was observed a sudden reversal of the effect towards the prestimulus state. A recruitment phenomenon was also observed, i.e., a late additional poststimulus increase in the effect prior to return to prestimulus state. A long-term adaptation was also detected when the duration of the phenomena was examined. It is suggested that the observed phenomena reflect the capacity of the cerebral circulatory system to undergo changes in the blood supply, i.e., in rate of blood flow and/or blood volume, independently, through the agency of neurogenic mechanisms. The localized changes described here were observed at different discrete brain sites as relatively fast, joint or even independent events, and this is highly suggestive of neurally mediated effects.

Participation of oxygen in the local control of skeletal muscle microvasculature.

The control of the local supply of oxygen to a skeletal muscle vascular bed was analyzed by: (1) determining if a relative oxygen lack causes vascular dilation, (2) ascertaining the vascular elements responsible for the dilation, and (3) attempting to elucidate the mechanism of the dilation. When the concentration of oxygen in the inspiratory air was reduced from that in room air to 18% without increasing the carbon dioxide concentration or inducing a fall in systemic arterial blood pressure, a dilation significant at the 5% level was observed in the terminal arterioles, the metarterioles, and the distribution arterioles of the cremaster muscle of the rat; all of these vessels were oriented transversely to the skeletal muscle fibers and had diameters of less than 40µ. The magnitude of the dilation, expressed as a percent of the control diameter, was inversely related to the vessel's average control diameter. No significant dilation was noted in the precapillary sphincters or the major arterioles with cont...

On the Nature and Etiology of Vascular Ectasias of the Colon

Vascular lesions of the right colon are being diagnosed increasingly as a cause of lower intestinal bleeding, but their nature and occurrence, primarily in the elderly, remains unexplained. Colons from patients with clinical and angiographic diagnoses of cecal vascular lesions were studied by injection and clearing, and by histological sections. In all injected specimens one or more mucosal vascular ectasias were identified. The mucosal lesions appeared to be secondary to dilated tortuous submucosal veins which were the more prominent feature and were often present without the mucosal ectasia. This suggests that ectasias are caused by chronic, intermittent, low grade obstruction to submucosal veins with dilation and tortuosity initially of submucosal veins, then of venules, capillaries, and arteries of the mucosal vascular unit. Ultimately, precapillary sphincters lose their competency, producing small arteriovenous communications. The concept that ectasias are degenerative lesions was evaluated by studying 15 right colons resected for carcinoma with no history of bleeding. Mucosal ectasias were identified in four colons and submucosal ectasias in eight. These investigations suggested that these lesions: (1) are vascular ectasias developing as a degenerative process of aging, (2) are present with or without bleeding in a significant portion of the population over 60 years of age, (3) are multiple more often than single, and (4) may represent the commonest cause of major lower intestinal bleeding in the elderly.

An analysis of interstitial fluid pressure in the web of the bat wing

A mathematical theory of interstitial fluid motion and capillary exchange is developed in order to understand and explain measurements of capillary and interstitial fluid pressure in the bat wing, in which a high degree of vasomotor activity occurs. As a result of precapillary sphincter activity, fluid is alternately filtered and reabsorbed from the capillary, and previous studies of related steady problems by the author suggest that the interstitial fluid pressure should oscillate with time. Wiederhielm and Weston did not observe such fluctuations when they measured tissue pressures near the capillaries. This apparent paradox is resolved in the present paper by including unsteady effects. It is shown that pressure oscillations are predicted, but because of the very high vasomotor frequency they die out within a very short distance from the capillary wall. The capillary pressure measurements of Wiederhielm and Weston are also explained in terms of precapillary sphincter activity.

Coronary intercapillary distance during growth: relation to PtO2 and aerobic capacity.

Intercapillary distance (ICD) was measured in left ventricles of rats beating in situ. Between 40 and 400 days of age, left ventricular weight increased threefold and ICD increased from 12.5-19.5 mum. ICD could be decreased by at least 2 mum at all ages studied. The number of capillaries which must be recruited to reduce ICD by 2 mum fell from 1,200/mm2 at 40 days to 280/mm2 at 400 days. Ventricular growth did not affect the O2 sensitivity of precapillary sphincters or the uniformity of capillary spacing. Calculations indicate that under basal conditions tissue PO2 (Pto2) in subepicardium is about the same at 40 and 400 days, even though VO2 per gram, capillary density, and ICD change twofold, twofold, and 7 mum, respectively. Nevertheless, as the ventricle grows, capillary recruitment becomes progressively less effective in defending Pto2 under conditions of stress. Diminished coronary capillary compensation for stress may, in part, account for the effect of age on the maximum aerobic capacity of the whole animal.

Influence of sympathetic nerves on oxygen uptake or resting mammalian skeletal muscle,

Gracilis muscles of anesthetized dogs were isolated and perfused with blood at constant flow. Oxygen uptake (Vo2) was measured by spectrophotometry of paired arterial and venous samples and monitored by continuous recording of HbO2 saturation. The sympathetic chain, connected to the isolated muscles, was stimulated electrically with supramaximal pulses. High frequencies (8-16/s) increased vascular resistance (R, ratio to control 1.86 +/- 0.6 SEM) and decreased Vo2 (0.61 +/- 0.02). Both effects could be maintained 10 min or longer. After stimulation there was an increase in Vo2, which could be less than equal to, or greater than the O2 deficit, depending on the stimulation frequency, the period of stimulation, and the blood flow. Low frequencies (0.5-4/s) increased R (1.39 +/- 0.04) and increased Vo2 during (1,18 +/- 0.03) and after stimulation. In several experiments there was an initial decrease in Vo2 which changed to an increase during the stimulation period while R remained elevated. These observations indicate that the decrease in Vo2 is due to closure of precapillary sphincters, whereas the increase is a direct effect on cell metabolism.

Intercapillary distances and capillary reserve in right and left ventricles: Significance for control of tissue pO 2

Distances between capillaries perfused with erythrocytes were measured by stopmotion microcinematography in rat hearts beating in situ. In 18 animals mean intercapillary distance (ICD) was 14.44 μm in the left ventricle and 15.47 μm in the right. These values correspond to about 2815 and 2530 perfused capillaries/mm 2. respectively. The difference in ICD is statistically significant. Calculations indicate that the shorter diffusion path in the working left ventricle has a significant effect on O 2 transport. On the other hand, minimum ICD is longer and maximum capillary density is smaller in the left ventricle. Thus a larger fraction of the available capillaries is utilized in the normal, working left ventricle. The estimated capillary reserve is 750/mm 2 in the left ventricle and 1500/mm 2 in the right. The shorter ICD in the beating left ventricle appears to reflect control of coronary precapillary sphincters by local tissue pO 2.

Defining the precapillary sphincter

Past and present use and abuse of the term precapillary sphincter is reviewed. The advantages of a uniform and functional definition are described, and a definition that is consistent with current information is proposed.

Role of resistance and exchange vessels in local microvascular control of skeletal muscle oxygenation in the dog.

The effects of reduction in perfusion pressure, arterial hypoxia, muscle contraction, and adrenergic stimulation on the hindlimb muscle circulation were studied. Under normal conditions (venous PO2 greater than or equal to 40 mm Hg), oxygen delivery to the muscle was maintained mainly by large increases in the capillary exchange capacity and the oxygen extraction ratio in accord with tissue demand following the application of the above stresses. The participation of the resistance vessels under these conditions was minimal. The prevailing venous oxygen tension then was reduced by several means and the response of vascular resistance and capillary exchange capacity to the same stresses was reexamined. At the lower prevailing venous PO2, the sensitivity of the resistance vessels to metabolic and hemodynamic disturbances was greatly increased. Consequently, blood flow autoregulation, functional hyperemia, and hypoxic hyperemia were more intense when venous oxygen tension was low. In contrast, the contribution of exchange capacity was diminished, probably owing to the fact that most of the capillaries already are open at low venous PO2. These data suggest that the locus of local microvascular control of muscle oxygenation shifts from the normally more sensitive precapillary sphincters to the proximal flow-controlling arterioles as the prevailing venous oxygen tension falls. Yet, although the relative contribution of the resistance and exchange vessels to intrinsic regulation of tissue oxygenation is related to the prevailing venous oxygen tension, the two compensatory mechanisms operating in concert maintain tissue PO2 above the critical level over a wide range of stresses.

Dopamine effects on the intestinal circulation

The effects of intra-arterial infusion of dopamine on superior mesenteric artery blood flow, intestinal flow, intestinal oxygen consumption, and capillary density were studied in anesthetized dogs before and after blockade of dopamine receptors with haloperidol and after beta-adrenergic receptor blockade with propranolol. Mesenteric blood flow to a distal segment of the small intestine was measured with an electromagnetic blood flow-meter and intestinal oxygen consumption was calculated from the measured arteriovenous oxygen difference across the intestine and total blood flow. Intestinal capillary density was estimated from the clearance of 86Rb. In normal animals prior to dopaminergic or beta-adrenergic blockade, dopamine caused a dose-related decrease in mesenteric blood flow, intestinal oxygen consumption, and 86Rb clearance. Only the lowest dose of the drug, 1 mug/Kg.-min., did not significantly change the intestinal capillary density. In dogs pretreated with the dopamine receptor, antogonist, haloperidol, dopamine (20 mug/Kg.-min.) caused a significant increase in blood flow and oxygen consumption and did not significantly alter the number of perfused intestinal capillaries. These increases in haloperidol-blocked animals administered dopamine were reversed by propranolol. Our results indicate that dopamine caused smooth muscle contraction in mesenteric arterioles and precapillary sphincters, thereby producing intestinal ischemia and hypoxia. These findings with haloperidol and propranolol indicate that dopamine stimulates at least two different receptors in the canine mesenteric vascular bed: a constrictor receptor blocked by haloperidol and a dilator receptor blocked by propranolol.

Beta adrenergic dilator component of the sympathetic vascular response in skeletal muscle. Influence on the micro-circulation and on transcapillary exchange.

A neurogenic beta-adrenergic vasodilatation in skeletal muscle has been indicated by some recent investigations. The present study describes the extent to which this neurogenic beta-dilator mechanism contributes to the integrated vascular response in consecutive sections of the muscle vascular bed during sympathetic nerve activation. This was done by studying the vascular reactions to graded sympathetic stimulation (1-16 Hz) before and after beta-adrenoceptor blockade. Beta-blockade did not influence significantly the sympathetically induced changes of total muscle vascular resistance or capacitance. Vascular tone in the "micro-vessels" during stimulation was, however, clearly more pronounced in the beta-blocked than in the non-blocked region, as revealed by segmental resistance analysis and by determination of precapillary sphincter tone (CFC). In addition, beta-blockade markedly reduced the net transcapillary absorption of extravascular fluid evoked by nerve activation. This effect could be ascribed to the mentioned influence on the precapillary sphincters, leading to a decrease of the number of capillaries available for transcapillary exchange, and to a limitation of the nerve induced fall of capillary hydrostatic pressure. The described effects of alpha-blockade were observed at all rates of sympathetic stimulation.--The conclusion was reached that the beta-adrenergic dilator component of the sympathetic vascular response in skeletal muscle significantly modifies the alpha-adrenergic constriction in the micro-vessels. It is suggested that, in the intact organism, this neurogenic beta-dilator mechanism is primarily aimed at improving the transcapillary exchange.

Effects of vasoconstrictors on intestinal vascular resistance and oxygen extraction.

To delineate the mechanism through which vasoactive compounds alter intestinal oxygen consumption and to determine the pharmacological nature of the receptors involved, we quantitated the effects of vasoconstrictors on arteriovenous oxygen difference and on vascular resistance in isolated constant-flow perfused canine small bowel. Norepinephrine (NE) and sympathetic stimulation (SS) increased vascular resistance and depressed O2 extraction. These effects were not altered by beta-blockade, but were abolished by alpha-blockade. Since capillary filtration coefficients at constant-pressure perfusion and 86Rb extraction at constant flow are reported to diminish during NE and SS, it follows that these agents reduce O2 extraction by an alpha-adrenergic closure of precapillary sphincters. Vasopressin had similar effects which were not affected by adrenergic blocking agents. Epinephrine (Epi) in high doses or after propranolol produced the same effects as NE and SS. By contrast, Epi in low doses increased O2 and 86Rb extraction. This response to low doses of Epi was not affected by phentolamine, but was reversed by propranolol. We conclude that Epi in high doses or after propranolol depresses intestinal O2 extraction by the same mechanism as NE and SS, but the mechanism through which Epi increases intestinal O2 extraction is unclear.